In the past few decades, ultrasound has become the primary imaging procedure for an increasing number of conditions. Ultrasound imaging is an integral part of the practice of obstetrics, gynecology, radiology, cardiology, neurology and neurosurgery, pediatrics, gastroenterology, urology, angiology, surgery, and internal medicine. In obstetrics, ultrasound is increasingly used for applications such as the assessment of gestational age and the diagnosis of placenta previa, multiple gestations, fetal growth retardation, and certain fetal structural abnormalities such as spina bifida and hydrocephalus. Diagnostic ultrasound has also proved useful in antenatal surgery for fetal diseases.

There is no doubt that a spectacular improvement in ultrasound imaging quality contributed to the rapid increase in its use as a diagnostic tool. Also, the introduction of the linear array real-time scanner in the 1970s led to a significant increase in the amount of ultrasound imaging performed during pregnancy. Recent advances in real-time scanners include the introduction of duplex systems, which combine real-time imaging with pulsed (including color) Doppler ultrasound. These systems made possible the measurement of fetal and uteroplacental blood flow. Information on that flow may become one of the most important obstetric applications of diagnostic ultrasound.

As a result of these advances, a rapidly increasing number of pregnant women have been exposed to ultrasound. Over a decade ago, about 40% of all pregnant women in the United States had undergone routine scanning.¹ However, there are reasons to believe that today this number is significantly higher: the corresponding rate of ultrasound exposure in most western European countries is now about 80%; in West Germany, virtually all babies are exposed to ultrasound in utero.

Because there is potential for the fetus to have long-term adverse effects from exposure to ultrasound,² it is more than relevant to ask, “How safe is ultrasound?” It is well established that under certain conditions ultrasound can lead to undesirable side effects.^3,4,5,6,7 Therefore, it is unrealistic to expect that the answer to this question can be a simple “yes” or “no.” Rather, the question to be answered should be, “Is diagnostic ultrasound safe as presently used in clinical practice?”

The main goal of this chapter is to summarize the available knowledge regarding whether ultrasound energy produces bioeffects at the levels currently used with commercial diagnostic equipment.

It must be stressed at the outset of this review that, to date, no evidence has been found of harmful effects of ultrasound in humans at clinically used exposure levels. However, new applications of and new advances in diagnostic imaging regularly prompt discussions on its safety and prudent use. Common to these discussions is that they call for avoidance of unnecessary exposure.^7,8,9,10 Also of concern is that although there is no reason to believe that there are risks related to ultrasonic exposure, there are many inexpensive ultrasonic scanners throughout the world. Therefore, there is an ongoing need to disseminate the knowledge of interactions between ultrasound energy and biologic tissue and to identify the potential conditions for bioeffects.^7,9,11

It is appropriate to note that any modern literature search on ultrasonically induced bioeffects will result in a list containing hundreds of papers and reports on the topic. Because the literature on this subject is enormous, only those papers that are considered to be relevant for this review are discussed here. In particular, attention is focused on data pertaining to mammalian tissue. Those readers who are interested in reviewing all data available are referred to excellent textbooks^12,13 or to several comprehensive reports.^{3,4,5,6,7,11,14,15,16,17}

Any informed discussion on bioeffects requires a basic understanding of the physical parameters involved and their relation to the observed effect. More specifically, the relation between the magnitude of the effect and the magnitude of the characteristic parameters of the ultrasound agent should be known. In addition, it is important to determine whether the effect will give rise to any concern. Otherwise, the significance of the experimental outcome can be misinterpreted easily and may lead to meaningless conclusions regarding the outcome's relevance to clinical practice.

To facilitate an understanding of these relations and to judge the significance of the findings reported in the literature properly, it is appropriate to start with a brief review of the relevant ultrasound parameters and the physical mechanisms of interaction between ultrasound and biologic tissue. This is followed by a summary of the range of acoustic output levels produced by the currently used clinical diagnostic machines and a succinct discussion of recent developments in the regulatory area. Briefly, these developments permit manufacturers to introduce a real-time on-screen display involving Thermal and Mechanical or Cavitational Index (TI and MI, respectively). These indices inform the user of the potential for ultrasonically induced bioeffects. Understanding the implications of such an on-system display is of vital importance for practitioners, including physicians, sonographers, and other allied health personnel applying ultrasound energy to patients. This is because the displayed information about the potential of bioeffects requires practitioners to make a direct decision as to the risks and benefits associated with the given clinical examination.^{7,8,9,10,11,12,13,14,15,16,17,18}

Next, a survey of the literature on biologic effects is given. As already noted, the biologic experiments that are discussed were carefully selected and limited to those that bear the closest resemblance to clinical exposure conditions. Special attention is given to human epidemiology studies; limitations and deficiencies of the current research on ultrasonically induced bioeffects are also discussed.

The conclusions focus on a critical summary of the current evidence on risks associated with ultrasonic exposure in diagnostic clinical examinations, including several relevant statements on in vivo mammalian bioeffects and safety by the American Institute of Ultrasound in Medicine (AIUM) Bioeffects Committee.¹⁷

It is widely accepted that there are two basic mechanisms, namely, thermal and nonthermal, by which ultrasound is known to affect biologic materials.^{3,12,13,14,17,18,19,20} Nonthermal mechanisms include cavitational and noncavitational effects, which are associated with certain mechanical aspects of the acoustic or ultrasonic field. These aspects can be described in terms of second-order phenomena, such as radiation pressure, radiation force, radiation torque, and acoustic streaming, and are comprehensively reviewed in other sources.^19,20

Because the data on second-order phenomena were obtained primarily by studying in vitro systems, and because their biologic significance is not immediately clear, attention is focused on thermal and cavitational phenomena. The following succinct description of these mechanisms should be satisfactory for the purpose of this chapter.

Thermal Mechanism

This mechanism is associated with the absorption of acoustic energy by tissue and the generation of heat. The thermal mechanism appears to be the best understood, and analytic models have been developed to predict the possible temperature elevation in tissue.¹⁸ These models relate acoustic energy to the associated temperature increase, provided that absorption coefficients for the tissues considered are known. A brief description of the physical and physiologic variables that play a role in the generation of this temperature elevation follows.

As an ultrasound beam traverses tissue layers, the rate of energy deposition is determined by the factors defined by the operational characteristics of the imaging system and the physical parameters of the tissue being imaged. The system's operating characteristics are functions of the imaging and/or Doppler mode being used, as well as of the focal characteristics of the transducer and its frequency. As an example of the way these characteristics influence energy transfer, one can note the difference in energy distribution between scanned modes such as B-mode and the pulsed-wave (PW) Doppler. More specifically, B-mode energy is distributed over a large volume, whereas in unscanned modes, such as PW Doppler, the acoustic energy is aimed along a single line. Similarly, a highly focused transducer has the potential for a highly concentrated energy deposition, whereas weakly focused transducers tend to spread the energy over larger volumes. Whether or not energy is deposited in a given tissue volume is determined by that tissue's absorption characteristics, which may vary significantly depending on the organ considered. For example, there is almost no absorption in liquids such as amniotic fluid, blood, and urine. However, an adult bone absorbs about 60% to 80% of the acoustic energy impinging on it.¹⁸ With fetal bone, there is a wide variation in absorptive behavior, depending on the degree of ossification. The clinical situation of greatest interest as far as thermal effects are concerned is a fetus in utero with an ossified bone structure and a mother with a thin abdominal wall. In such a case there is little attenuation of acoustic energy because of the thin layer of intervening maternal tissue, yet there is a high degree of absorption associated with the fetal bone.¹⁸

Local generation of heat per second in a volume of 1 cm³ can be calculated from the following expression:

where a(f) is the absorption coefficient in dB/cm (in most tissues this coefficient is proportional to the frequency), and I is the local average intensity per time unit in W/cm² (a more rigorous definition of intensity is given in the next section). The absorption coefficient is defined by the tissue characteristics, whereas the in situ intensity is determined by both the imaging system and the attenuation of the overlying tissues. The relation between the intensity in a given tissue layer and its absorption deserves a brief discussion here. A highly focused beam whose focal point is in amniotic fluid will not cause significant heating of the fluid simply because the absorption level of the fluid is low. In this situation, the a(f) of the above equation is relatively low, whereas the I has a relatively high value. The same beam with its very high focal intensity will cause a significant temperature rise if it impinges on ossified bone, which has an a(f) value that is significantly higher than that of amniotic fluid.

Another important determinant of local heating involves the degree of attenuation in tissue layers in front of the point of interest. An increased amount of attenuation in the overlying tissues decreases the energy available for conversion into heat. Thus, the use of fetal Doppler through a thick abdominal wall is less likely to cause a significant temperature increase than are examinations involving patients with thin abdominal walls.

Although the above discussion has concentrated on heat sources, there are at least two mechanisms of heat loss. Blood perfusion is an efficient mechanism for heat removal. In fact, the designers of hyperthermia systems have significant difficulties with it.²¹ The degree of blood perfusion varies between the tissue types: among the best perfused organs are the kidneys, heart, and brain, whereas bone and resting muscle are among the least perfused.²² Another cooling mechanism is due to heat conduction. The degree of thermal conductivity is relatively uniform among the tissues and is fairly close to that of water, with the exception of bone, which is highly conductive, and fat, which is a poor thermal conductor.²²

There seems to be an agreement that an in situ temperature rise to or above 41°C is considered hazardous in fetal exposures because it may lead to undesired effects. A more detailed discussion of the recent AIUM recommendations concerning possible thermal mechanism - related bioeffects is given in the closing section of this chapter.¹⁷

Experimental studies indicate that intact mammalian systems (in vivo) do not show a significant rise in temperature when exposed to pulsed imaging equipment.^3,12,17 However, the recently developed peripheral vessel pulsed and continuous-wave (CW) Doppler equipment, when used for a relatively long time (1 – 10 min), may be an exception.^17,23 Therefore, the Doppler system should be used with care, especially during the recently developed applications in which Doppler is used for the study of blood velocities in the umbilical cord and the fetus.

Cavitational Mechanism

The term cavitation refers to phenomena associated with the vibration and motion dynamics of small gaseous bodies when exposed to an ultrasound field.^12,17,20 In the first approximation, these gaseous bodies are treated as spherical cavities (microbubbles) about 1 μm in diameter. Such gaseous bodies may expand because of “rectified diffusion”^24,25 until their radius grows to the magnitude at which mechanical resonance takes place.

Near the frequency of mechanical resonance, the vibration amplitude of the bubble wall is large and may range up to 100 times the value of the radius at equilibrium (i.e., when the sound field is turned off).²⁶ If the bubble does not collapse during the ultrasound exposure, the condition is referred to as stable cavitation, in contrast to inertial (collapse) cavitation (formerly known as transient cavitation⁵), during which the vibration amplitude of the bubble wall increases so much that the bubble implodes. This implosion generates highly localized shock waves and is also associated with extremely high local temperatures (up to 10,000°K).²⁷ In addition to the temperature elevation, the implosion results in the generation of free radicals such as hydroxyl radicals and hydrogen. These radicals are very active and may lead to some undesired biologic changes, such as spontaneous biochemical reactions within the tissue.

In this context it is worthwhile to point out that lung hemorrhage has been observed in mice after exposure to ultrasound waves with relatively low peak pressures of 1 to 2 MPa. More specifically, cavitation-related events were reported as a mechanism leading to lesions in the lung tissue of adult mice.²⁸ The hemorrhage of lung tissue in mice occurred as a result of exposure to 1-MHz, 10-μs pulses of about 1 MPa pressure amplitude. Also, the lung tissue damage was observed in the lungs of monkeys exposed to 3.7 MPa using a commercial diagnostic ultrasound imaging device operating at the maximum output in combined pulsed and color Doppler mode.²⁹ This is of interest because monkey represents a biologic model closely resembling human. This suggests that the alveoli may act as cavitation nuclei and that caution should be exercised in cases in which the ultrasound interacts with lung tissue. Although only a limited number of primates were used in the study, these results are important because lung hemorrhage was observed at clinically relevant exposure conditions. Also, although these results have not yet been independently confirmed, this study suggests an increased potential risk when frequent cardiac examinations are performed in the neonates. It is appropriate to point out here that certain tissues may be more prone to cavitation-like events than others. Thus, no kidney hemorrhage in mice was observed at peak positive pressures of 9 to 10 MPa and negative peak pressure amplitudes of 4 to 5 MPa at frequencies of 1.2 and 3.8 MHz.³⁰ Thus, it appears that in kidney tissue there are no nuclei to sustain a gas body.

The bioeffects observed in the study by Tarrantal and Canfield²⁹ and the study by Carstensen and colleagues³⁰ are also relevant to the situation in which the fetus undergoes prolonged exposure to ultrasound in an early stage of pregnancy. Therefore, the ultrasound examination time should be minimized, consistent with the requested diagnostic information.

Inertial cavitation leading to severe tissue hemorrhage also has been experimentally observed during therapeutic treatment of the kidney using an extracorporeal shock-wave lithotriptor.³¹

Although of only peripheral interest to the present discussion, it should be recognized that a sufficiently high negative peak amplitude of the ultrasonic wave can cause severe damage to the tissue. A typical pulse generated by a lithotriptor is shown in Figure 1. The negative pressure amplitude of the typical lithotriptor pulse (see Fig. 1) may be of the same order of magnitude as the corresponding pressure amplitude of the pulses used in diagnostic ultrasound (see Acoustic Output Levels).

During stable cavitation, the vibration amplitude of the bubble wall may set up microflow (microstreaming). The theory of microstreaming is well developed and is well described by Nyborg.³² The theory predicts that the microstreaming can generate shear stress that acts on adjacent bodies such as cell membranes.^5,32,33 If the shear stress is sufficiently large, it may cause breakage of the cell membrane.^32,33 It may be argued that cell membrane breakage can also happen during exercise such as jogging. Nevertheless, the breakage, even if unimportant from a biologic point of view, occurs because of the body's response to an external agent, and therefore it should not be totally dismissed. Although phenomena resembling stable cavitation have been reported in in vivo experiments, it appears that they occurred under exposure conditions not directly relevant to diagnostic imaging.²⁸

As already mentioned, interpreting the data on the safety of ultrasound requires some knowledge of the basic terminology of key ultrasound field parameters, such as acoustic pressure or intensity. Thus, before the review of bioeffects observed, it is essential to briefly clarify the nomenclature used in ultrasonic exposimetry and to introduce acoustic field parameters relevant to ultrasound bioeffects.³⁴

It is common practice to relate the bioeffects of ultrasound to intensity. Therefore, it is important to distinguish between spatial peak, spatial average, temporal (or time) peak, and temporal average intensities (Fig. 2). In addition, spatial peak, pulse average intensity (I_SpPa) is often used. In fact, an I_SpPa intensity of 190 W/cm² constitutes a limit for temporal peak output levels of diagnostic ultrasound equipment.³⁵

Spatial peak (Sp) intensity is defined as the maximum point intensity measured in the field of a radiating transducer; spatial average (Sa) intensity is the average of the intensity across a given area; temporal peak (Tp) intensity is the maximum intensity for a given time interval; and time average (Ta) intensity is the average of the intensity for a given time interval. Rigorous definitions of these parameters can be found in several publications.^34,35

It should be pointed out that a combination of spatial and temporal intensities is needed to relate an observed bioeffect to ultrasound field parameters. Thus, the widely known AIUM publication¹⁷ refers to the spatial peak, temporal average (SpTa) intensity. Also, it should be noted that although bioeffects are conventionally related to the acoustic intensity or I (units: W/cm²), the field parameter currently gaining attention is acoustic pressure P (units: pascals or Pa; 10⁵ Pa = 1 bar ~ 1 atmosphere), because it is often the primary parameter measured. Moreover, knowledge of peak negative pressure amplitude is needed to determine the value of the MI (see The Output Display Standard).

All intensities are found by analyzing the pressure - time waveform recorded at the prescribed position in the ultrasound field in water, the beam profile taken at this position, and the measurements of focal distance and imaging frequency.³⁵ The acoustic pressure - time waveform (Fig. 3), if measured with a calibrated receiver, contains the information required to determine most of the ultrasound exposure parameters. Thus, the waveform contains information about the working frequency of the imaging transducer, positive and negative peak pressures, the pressure gradient, and possible nonlinear propagation phenomena.^36,37

From the analysis of the waveform, characteristic times (such as effective pulse duration time) and ultrasound field intensity parameters (such as I_m [instantaneous maximum],³⁵ SpTp [spatial peak, temporal peak], SpTa [spatial peak, temporal average], SaTa [spatial average, temporal average], and SpPa [spatial peak, pulse average] intensities) can be determined.^3,34,35

In addition to these intensities, the beam pattern distribution, total acoustic power (W), pulse repetition rate (PRR), and imaging frequency are needed to adequately determine ultrasound field parameters. All of these parameters can be determined by using calibrated miniature ultrasonic hydrophone probes. The probes are made of piezoelectric polymer such as polyvinylidene fluoride (PVDF) and exhibit excellent acoustic properties. The most common designs use either the original hoop membrane approach or the needle-type construction.³⁸ When properly designed, the probes have proved suitable as reference hydrophones with good spatial and temporal resolution. With their flat (to within ± 1.5 dB) frequency response and uniformity of voltage sensitivity to beyond 15 MHz, they are uniquely suited to the measurement and characterization of ultrasound fields and acoustic sources. In addition, the characteristic features of the probes, such as well behaved, generally predictable directivity patterns, excellent linearity over a wide range of pressures (up to 100 MPa in the biomedical ultrasonics range of frequencies), and long-term stability, make them suitable for the comprehensive characterization of both pulsed and continuous-wave ultrasonic fields. These hydrophones are pressure-sensitive devices; therefore, conversion of the pressure into intensity units is usually done under the tacit assumption that the plane wave approximation holds (i.e., that intensity is proportional to the square of the pressure amplitude and inversely proportional to the product of density and sound velocity).

Calculation of different intensities is fairly complex and involves squaring and integration of the pressure - time waveform. The steps needed to determine intensities and other relevant exposure parameters from the analysis of the waveform are shown in Figure 3. Detailed algorithms that allow SpPa, SpTa, and I_m intensities to be calculated in water and in situ can be found in the 510(k) Guide for Measuring and Reporting the Acoustic Output of Diagnostic Ultrasound Medical Devices.³⁵

An additional ultrasound field parameter to be determined is the total acoustic power generated by the imaging transducer. Calculation of the total power requires knowledge of the beam profile taken in the plane corresponding to the focal distance at which the waveform of Figure 3A was recorded.

Complete ultrasound dosimetry also requires information on exposure time, including dwell time. The dwell time is defined as the time during which the ultrasound beam (more specifically its focal zone) remains at the same site of the body in usual clinical practice.

Each expression of intensity mentioned above serves a different purpose.³⁴ Briefly, the I_SpPa is a measure of the ultrasound energy associated with a single pulse, and I_m intensity characterizes the maximum instantaneous energy in the period of the pulse duration. The I_SpTa corresponds to the energy averaged over a period of time and is proportional to the PRR. Although a typical imaging system has a PRR (also referred to as pulse repetition frequency) on the order of 1 kHz, a PRR as high as 20 kHz may be used in blood flow velocity measurements using Doppler devices. The rationale for determining peak negative and peak positive pressure amplitudes and the intensity parameters shown in Figure 3 is their potential for producing bioeffects. A comprehensive discussion of this issue is given in the article by Nyborg and Wu.³⁴

Once the definitions of the different acoustic intensities are known, the data available on the acoustic output of ultrasonic equipment for imaging and Doppler applications can be summarized. The acoustic output levels of the diagnostic devices quoted here were compiled from recently published data and are listed in Table 1, Table 2 and Table 3.³⁹ The Doppler instruments measured included CW Doppler units for cardiovascular investigations, fetal monitors, stand-alone pulsed Doppler equipment, color Doppler, and duplex scanners working in Doppler mode, all in the frequency range of 2 to 8 MHz. Measurements were carried out in water and revealed that pulsed Doppler equipment could generate SpTa intensities that exceeded 100 mW/cm², with a maximum of 4520 mW/cm².³⁹ (The maximum SpPa intensity for pulsed Doppler equipment was about 770 W/cm²).³⁹

TABLE 1. Highest Values of Acoustic Parameters Encountered at the Output of Pulsed Doppler Equipment (Water Values)

TABLE 2. Highest Values of Acoustic Parameters Encountered at the Output of Continuous-Wave Doppler Equipment (Water Values)

TABLE 3. Highest Values of Acoustic Parameters Encountered at the Output of Diagnostic Pulse-echo Equipment (Water Values)^17,39

The output of some CW cardiovascular Doppler devices produced intensity levels on the order of 850 mW/cm², whereas fetal monitoring equipment intensities were on the order of 30 mW/cm². Table 1 and Table 2 compile the highest intensities measured at the output of pulsed and CW Doppler equipment, respectively. Table 3 summarizes maximum output levels encountered at the output of clinical pulsed echo equipment.

Before a review of the clinical evidence for ultrasonically induced bioeffects can take place, it is important to briefly discuss the clinical implications of the recently implemented Output Display Standard (ODS).^7,17,35 As a result of discussions that involved the Food and Drug Administration (FDA), the AIUM, and the National Electrical Manufacturers Association (NEMA), in 1994 the FDA revised its guidance on diagnostic ultrasound 510(k) submissions to allow the use of the MI in place of the I_SpPa in determining substantial equivalence of devices. This revision assumes that on-system displays¹⁷ of numerical indices, including MI and TI, will inform the user about the potential for either thermal or nonthermal bioeffects associated with the actual examination settings of the imaging system. This enables the clinician to increase acoustic power output beyond the existing FDA guidelines when clinically warranted. Before the 1994 FDA revision, such an increase was not possible. The maximum available acoustic output was limited by the manufacturer's software, which would not allow the output to exceed FDA guidelines for maximum exposure. It must be stressed that with the implementation of the ODS, diagnostic ultrasound systems can have a higher output limit. With the higher limits comes the potential for increased risk to the patient, so the clinician must make a careful risk/benefit analysis. Therefore, the purpose of the ODS is to help the clinician implement the ALARA (as low as reasonably achievable) principle and minimize the potential for bioeffects.

In the following pages, the thermal and mechanical indices are defined and the potential for added diagnostic and clinical benefits is briefly discussed. Additional comments on the indices are given in the Conclusions section. A more comprehensive treatment of the different tissue models (including homogeneous tissue, soft tissue, and bone tissue) used in the development of the indices is found in Medical Ultrasound Safety,⁷ Bioeffects and Safety of Diagnostic Ultrasound,¹⁷ and the article by Thomenius.¹⁸

The TI, which should be displayed during all unscanning equipment operations (i.e., M-mode, CW, and PW Doppler, as well as color Doppler), is considered to be best suited as a predictor of possible thermal effects. The MI has been developed as an indicator of the potential cavitation-like phenomena related to B-mode operation. The TI is defined as: TI = W₀/W_deg, where W₀ is the acoustic power output of the probe under a given operating condition and W_deg is the estimated acoustic power output necessary to raise the target tissue temperature by 1°C.

The MI is considered to be a suitable predictor of possible cavitation-like phenomena. MI is equal to (ρ_r.3/f₀)^1/2, where ρ_r.3 is the maximum derated value of peak rarefactional or negative pressure amplitude and f₀ is the center transducer frequency. It should be noted that whereas the ρ_r.3 values associated with lithotriptors (see Fig. 1) and diagnostic ultrasound instruments often are of the same order of magnitude, the increased potential for the occurrence of cavitation with lithotriptors is associated with their lower frequency content of the shock waves (about 0.5 – 2 MHz).

In general, the bioeffects literature can be divided into two classes: one based on the epidemiology of the large number of ultrasound examinations performed both clinically and as laboratory experiments, and another in which a causal relation between bioeffects and the applied acoustic energy is developed. Both classes are discussed below.

Effects of Ultrasound on Mammalian Tissues In Vivo

Simple in vitro models, such as cells, are often used in the search for biologic effects to gain an understanding of the possible mechanisms of interaction between ultrasound and biologic tissue. The results of the research on biologic effects in nonmammalian species, such as insects, amphibians, and avians, indicate that studies on these relatively simple organisms are helpful in understanding the mechanisms of interaction between ultrasound and biologic systems.¹⁵ However, from the point of view of this work, studies of mammalian species are of more relevance. The examples chosen for the present discussion pertain mainly to in vivo insonation of mammalian tissue and include exposure conditions at clinically relevant frequencies. Most of the bioeffects studies were performed on small rodents, such as mice or rats. Although these animals constitute a fairly inexpensive model for in vivo bioeffects studies, the extrapolation of experimental results to humans is not immediately obvious. A very comprehensive review of the effects of ultrasound on mammalian development was prepared by Sikov.¹⁶ He evaluated bioeffects depending on gestational age and thus attempted to extract information on the relation between exposure parameters and stage of development at exposure.

Because this approach seems useful for drawing some conclusions about the adverse effects of diagnostic ultrasound in prenatal practice, it was adapted in the following discussion of bioeffects findings.

EARLY STAGE.

Several researchers studied the influence of ultrasound exposure in the period before implantation. In the CW studies, Takeuchi and co-workers⁴⁰ used pregnant rats exposed to a 2.5-MHz ultrasound field on the second and third day of gestation, at spatial average intensities of 150 mW/cm². No increase in prenatal mortality was found. Similarly, no increase in the rate of postnatal malformation was found after 20-minute exposures. These results are not surprising in view of the fact that absorption in the embryonic tissue is lower than that of the surrounding tissue. Therefore, it is likely that more heat was generated in the vicinity of the embryo than in the embryo tissue itself.

Stolzenberg and associates⁴¹ exposed pregnant mice to 2-MHz of CW ultrasound in the first 3 days of gestation. A 1-inch (about 25 mm) planar source transducer was used, and the spatial average intensity was determined to be 1 W/cm². A decreased uninterrupted pregnancy rate was noted after exposure for 5 minutes on the third day and after exposure for 200 seconds on day zero. Also, a reduction in fetal weight after delivery was observed at thresholds corresponding to exposure for 100 and 200 seconds on day zero and 200 and 400 seconds on the first day. In another series of studies,⁴² ultrasound exposure led to damage of maternal tissue, which was reflected in increased mortality, decreased weight gain, and paralysis of the pups.

Thus, it appears that in vivo exposure to CW ultrasound at spatial average intensities below 1 W/cm² does not affect embryos at the early stage of gestation. However, limited data suggest that levels of ultrasound of 1 W/cm² may lead to undesirable changes in maternal tissue.

The application of ultrasound in guided oocyte aspiration for in vitro fertilization and embryo transfer is rapidly growing. Therefore, the recent studies aimed at determining the interaction between ultrasound exposure and successful fertilization are included in this discussion.^43,44 In general, the clinically available data on ultrasound exposure of oocytes during meiosis are confusing. Although some researchers reported a deleterious effect on the fertility of patients undergoing artificial insemination (they claimed a reduction in the cumulative rate of pregnancy),⁴⁵ others claimed an increase in the success rate, allowing ultrasound monitoring of follicular growth.⁴⁶

An attempt to clarify this ambiguity was described by Mahadevan and colleagues.⁴⁷ Their study sought to determine how oocytes obtained under ultrasound guidance affected the pregnancy rate. The results obtained at 3.5 MHz suggest that exposure of human oocytes to ultrasonic waves during the different phases of meiosis does not significantly influence the developmental potential of the in vitro fertilized embryos. Unfortunately, except for ultrasound frequency, these researchers did not give any of the relevant exposure parameters discussed earlier.

ORGANOGENESIS.

McClain and associates⁴⁸ exposed rats to 10 mW/cm² CW Doppler ultrasound for up to 2 hours at frequencies of 2.25 and 2.5 MHz. The fetuses were examined on day 20, and no consistent increase in mortality was observed, nor did the authors detect any other abnormalities.

Stolzenberg and co-workers⁴¹ reported a decrease in the uninterrupted pregnancy rate of mice exposed between days 6 and 8 to a spatial average intensity of 1 W/cm². They reported statistically significant fetal weight reductions for exposures longer than 140 seconds. More evidence of the possibility of ultrasonically producing embryolethal effects during organogenesis has been described.^49,50,51,52 Sikov and colleagues^49,50,51,52 exposed an exteriorized rat uterus to three frequencies (0.8, 2, and 3.2 MHz) at day 9 and evaluated the offspring at day 20. The exposure was performed at different intensity levels, with exposure times at 5 or 15 minutes. No effect on fetal weight was observed, even at spatial average intensities as high as 30 W/cm², but prenatal mortality at 15 to 20 W/cm² (spatial average) clearly increased with increasing exposure time. The cause of this was ascribed to a thermal mechanism.

FETAL BONE HEATING.

Several researchers have investigated exposure conditions in which the ultrasound energy was impinging on a bone embedded in tissue with relatively little absorption or attenuation. This situation is particularly relevant in obstetrics, because the developing fetus is exposed to diagnostic ultrasound. Carstensen and associates⁵³ insonified exposed mouse skulls that had thermocouples implanted. Both adult and young mice were used. The results were reproducible, with the older mice yielding a steady temperature rise of 5.6 ± 0.3°C with a focal intensity of 1.5 W/cm². In the first 15 seconds of ultrasound application, the temperature rose to about 75% of the final value. Comparison of these results with the theoretic predictions obtained from an appropriate tissue model¹⁸ indicated an agreement to within 20%; however, the theoretic transient response indicated the possibility of a considerably faster rate of temperature increase-the 75% was predicted to be achieved within 5 seconds of exposure. These results indicate that there may be a reason for concern, especially with the rate of temperature increase. Also, at this rate of heating, the exposure time should be limited to about 1 minute.¹⁸ If the temperature increase had been, for example, 7°C, the exposure time necessary for a bioeffect to occur would have been 15 seconds. It cannot be ruled out that during an actual examination, the acoustic beam might be held stationary for such a period.

POSTNATAL DEVELOPMENT.

Equally important in determining the safety of diagnostic ultrasound is knowing the influence of prenatal ultrasound exposure on postnatal development. In a carefully devised study,⁵⁴ pregnant rodents were exposed to 500 mW/cm² spatial average intensity at 2-MHz ultrasound for 1 to 3 minutes, or to 1 W/cm² spatial average intensity for 40 to 60 seconds. No fetal mortality was observed; however, a weight decrease in the pups delivered was observed after exposure to 0.5 W/cm² for 180 seconds.

In another study, the effects of prenatal ultrasound exposure on adult offspring behavior in the Wistar rat were investigated.⁵⁵ The animals were exposed on days 15 through 17 and on 19 of gestation to a 5-MHz, 1-kHz pulse repetition rate and intensities (I_SpTp) of 500 and 1500 W/cm². The total exposure time was 35 minutes. Two hundred seventy-eight offspring were subjected on postnatal day 60 to two of four well-established behavioral tests. The animals were tested in random order within sexes. The results showed no consistent dose-related alterations in adult behavior due to prenatal fetal exposure.

Vorhees and co-workers⁵⁶ used a unique approach to study the possible teratogenic effects of ultrasound exposure. They eliminated the need for anesthesia (and therefore the possible complications caused by forced restraint) by training the rats to remain immobile during the ultrasound exposure. The animals were exposed to 0.1, 2, or 30.0 W/cm² (I_SpTa), 3 MHz CW, for about 15 min/day on days 4 through 19 of gestation. No dose-dependent changes in various maternal parameters, the incidence of malformation, or fetal weight were observed. In a follow-up study, Vorhees and colleagues⁵⁷ exposed rats to these levels of ultrasound for 10 minutes on gestational days 4 through 20. Although they did not observe exposure-related alterations in maternal parameters, offspring survival and growth, or neonatal psychophysiologic parameters, changes did occur in offspring adult behavior, in locomotor activity, and in two measures of the multiple-T water maze test performance at the highest dosage level.

In the studies aimed at determining the effects of ultrasound exposure on uteroplacental function, ter Haar and co-workers⁵⁸ found that a spatial peak intensity of 2 W/cm² at 3 MHz caused an exteriorized uterus to increase in frequency of contraction, which lasted for about 4 minutes after the ultrasound was turned off. They reported no increase in temperature and thus ascribed the increased rate of contractions to an unspecified nonthermal mechanism.

Placental function during ultrasound exposure was investigated by Kelman and associates.^59,60,61 In their experiments they insonified the placenta of a guinea pig with 2.5 MHz of ultrasound at different intensity levels and in both pulsed and CW modes. Functional changes were observed after 10 minutes of exposure at SpTp intensities of 30 W/cm² in pulsed mode (pulse length, 10 μs; PRR, 1 kHz) and SpTa intensities of 28 to 46 W/cm² in the CW mode.

Again, it appears that at sufficiently high intensity levels, ultrasound can affect vitelline blood flow and lead to increased uterine contractility and changes in placental function. However, the exposure levels far exceed those present in the clinical environment. Murrils and associates⁶² found that fetal Doppler monitoring did not influence fetal activity, which would be an indication of ultrasound effects on the perinatal nervous system.

Bioeffects Related to Hyperthermia

The evidence above indicates that there is a teratogenic effect of heat on the prenatal development of mammalian tissues. Experiments with cultured rat embryos stressed the importance of ambient temperature; no bioeffects were observed when embryos were exposed to pulsed ultrasound for 15 minutes at I_SpTa levels of 1.2 W/cm².⁶³ However, the same experiment repeated with the temperature elevated 1.5°C above normal (40°C) resulted in retardation of head growth. Although the outcome of this experiment cannot immediately be extrapolated to humans, it indicates that ultrasound exposure of a febrile pregnant patient under certain conditions might constitute an increased risk for potential bioeffects.

There are relatively few papers containing diagnostically relevant information on this subject; therefore, it is appropriate to draw attention here to a recent survey.⁶⁴ This survey established that no thermal bioeffects were observed at temperature elevations of 39°C, regardless of how long the ultrasound exposure lasts. However, for each increasing degree of temperature elevation, to stay within safety limits, the duration of ultrasound examination must be reduced by a factor of four. More specifically, the review indicated that the maximum safe duration for a temperature of 43°C is 1 minute, and for 42°C it is 4 minutes. Similarly, at 41°C the exposure time may be increased to 16 minutes, and at 40°C the duration of examination may be as long as 64 minutes. Based on the data available, the survey concluded that if the maximum temperature rise during the ultrasound exposure is kept less than 2°C, any biologic effect (in a febrile patient) is highly unlikely. It is possible to express the relation between the exposure time required for a bioeffect to occur and the associated TI, namely, t = 4 < (6 - TI). Thus, for a TI of 6, the exposure time should be limited to 1 minute. Similarly, a TI of 4 means that the exposure time should be less than 16 minutes (see Appendix).

Recent findings indicating that the ultrasound imaging transducer may act as a substantial heat source (Duck FA, unpublished observations) are also of interest. The temperature at a clinically operated Doppler transducer was reported to increase by 10°C when the Doppler was applied to skin with a standard coupling gel. Although tissue heating from the transducer is most likely limited to the tissue volume in the immediate vicinity of the transducer, this effect should be kept in mind for ultrasound examinations in which an endocavity (e.g., endovaginal) transducer is used, or when performing contact scanning of the neonatal brain or in ophthalmologic applications.

Bioeffects Related to Cavitation

A few relevant papers reporting lung hemorrhage in mice and in monkeys caused by cavitation-like phenomena have already been discussed under Cavitational Mechanism.^28,29 These papers describe significant biologic effects associated with gas body activation. The effects were produced in vivo in mammalian lung tissue in small rodents (mice) and in primates (monkeys). The bioeffects were observed at pressure amplitudes and pulse durations representative of those currently encountered at the output of diagnostic ultrasound equipment, particularly when used in pulsed Doppler mode. As previously noted, the results described in those papers are important for the present discussion because they led to a modification of the AIUM statement on “In Vivo Mammalian Bioeffects.” The statement, which was renamed “Non-Human Mammalian In Vivo Biological Effects,” emphasizes the importance of the MI.¹⁷

Recent data presented in the article by Dalecki and colleagues⁶⁵ indicate that, in general, threshold pressures increase with increasing frequency. The thresholds for hemorrhage in the intestine of adult mice ranged from about 1 MPa at 1 MHz to 3 MPa at 3 MHz (10-μs pulse duration, 100-Hz repetition rate).

To date there is no evidence that flowing cardiovascular blood will permit cavitation in vivo. Although there is some indication that microscopic gas bodies may exist in biologic tissue, there is no evidence that exposure of these bodies to the ultrasound levels similar to those used in clinical diagnostic practice will cause any significant bioeffects. However, it is conceivable that vibration of those bodies may introduce cell membrane stresses that can lead to extravasation of blood in lung tissue.⁵ This may indicate a need for appropriate modification during cardiovascular examinations and transesophageal echocardiography.

The above findings indicate that the body regions containing gas volumes are very sensitive to the potential side effects of ultrasound exposure and that biologic effects can be introduced by using a commercially available diagnostic imaging system in tissues containing gas volumes. Carefully designed studies are needed to assess any potential hazards with conditions that are typical for diagnostic ultrasound. Such hazards may also be associated with ultrasonic contrast agents injected into the vascular system.

To summarize, the thresholds for confirmed cavitation-induced biologic effects in mammalian tissues in the diagnostic frequency range of 2 to 8 MHz are above 1 MPa.¹⁷ All of the biologic effects that have been confirmed under diagnostically relevant exposure conditions involve tissues that are known to contain microscopic gas bodies. For tissues not containing gas (such as the kidney), no damage was observed at peak positive pressures on the order of 10 MPa.³⁰ Lung hemorrhage has been observed in neonatal and adult mice, rabbits, monkeys, and neonatal swine with diagnostically relevant ultrasound pressures ranging from 1 to 3 MPa. No damage was observed in the lungs of adult swine at pressures on the order of 5 MPa (see Appendix).^28,29

Epidemiologic Studies

The evidence of ultrasonically induced bioeffects in humans is perhaps the most important information from the clinician's point of view. As pointed out by Ziskin and Petitti,² “No matter how many laboratory experiments show a lack of effect from diagnostic ultrasound, it will always be necessary to study directly its effect in human populations before any definitive statement regarding risk can be made.”

There are extensive reviews of the literature on the epidemiology of human exposure to ultrasound.^1,3,6 As would be expected, the major thrust of these reviews is the assessment of the possible side effects of ultrasound exposure in utero. This is mainly because most pregnant women are exposed to ultrasound examination in the early stages of pregnancy and because any harmful effects to the fetus may last for years to come.

In general, few data pertaining to human ultrasound exposure are available. Some of the published data are reviewed briefly here. The experiments of O'Brien,⁶⁶ who observed that in utero exposure to ultrasound resulted in reduced birthweight in mice, prompted similar studies in humans. Bakketeig and associates,⁶⁷ in their randomized, controlled trial, reported that they were unable to find any effect of ultrasound on birthweight in humans. A similar conclusion was drawn from the earlier studies on the relation between ultrasound exposure and birthweight.⁶⁸

Although no fetal structural anomalies were observed in the recent studies performed by Stark and co-workers⁶⁸ and Bakketeig and colleagues,⁶⁷ Stark and associates reported somewhat disturbing findings in their retrospective follow-up examinations of 425 children exposed to ultrasound in utero and 381 unexposed children. They reported an increased risk of dyslexia; however, their study suffers from the fact that the subjects were not selected at random. No evidence has been found that ultrasound exposure in utero may lead to an increased rate of childhood cancer.^69,70 Likewise, no relation between in utero exposure and children with hearing deficiencies has been determined.⁶⁸

Deficiencies of the Bioeffects Studies

The data presented earlier indicate that the exposure of pregnant rodents to CW ultrasound at sufficiently high intensities during organogenesis can lead to undesirable biologic changes in the developing fetus. Also, recent evidence has emerged indicating that the body regions containing gas volumes may be particularly prone to potential side effects when exposed to sufficiently high pressure amplitudes.^28,29 Although the data were carefully selected to include only those studies that can be readily related to diagnostically relevant exposure conditions, it should be stressed that in most cases the bioeffects were observed at exposure conditions that were different from those typical of clinical diagnostic practice. Before 1990, most of the bioeffects observed were ascribed to the thermal mechanism of interaction between the ultrasound and biologic tissue, but in the past half decade it has been demonstrated that exposure to ultrasound produced by commercially available diagnostic imaging equipment can produce nonthermal, cavitation-like bioeffects in the lung tissue of primates.²⁹

Many bioeffects studies describe the effects of whole-body heating, which most likely acts through a mechanism that is not immediately comparable to ultrasound-induced hyperthermia. Few studies have been specifically designed to determine threshold values for abnormal embryonic or fetal development.⁶⁴ On the basis of the thermal criterion, a diagnostic exposure that produces a maximum temperature rise of 1.5°C above normal physiologic levels can be used without reservation in clinical examinations (see Appendix). However, a diagnostic exposure that produces an in situ temperature elevation to or above 41°C for 15 minutes should be considered hazardous to embryonic or fetal development. Any increase in the tissue temperature will act as a potentiating factor. Therefore, ultrasound examination in a febrile patient may constitute an additional embryonic and fetal risk.⁵

The reviews on human exposure clearly indicate that epidemiologic studies and surveys yield no evidence of adverse effects from diagnostic ultrasound, but they also point out several serious deficiencies of all the data available. These deficiencies are carefully discussed by Ziskin and Petitti.²

Ziskin and Petitti point out that the available results of epidemiologic studies are based on about 500,000 patient examinations that were collected from 179 users of clinical ultrasound. However, the results allow only a fairly cautious statement to be made, namely, that the users overwhelmingly believe that their experience with diagnostic ultrasound had been safe.

Ziskin and Petitti also note that all clinical studies on the possible harmful effects of ultrasound exposure to the fetus produced negative results. However, the acoustic outputs of the diagnostic instruments used were generally not known. In addition, the sample sizes (the number of patients included in the studies) were limited to a few hundred. In their careful assessment of the limitations of the epidemiologic studies, Ziskin and Petitti focus on the lack of information or simply inadequate ultrasound dosimetry. Also, the reasons for the examinations were not clearly stated, and sparse information is available on the number of examinations and the gestational age at the time of exposure. In addition, most studies were performed with pulsed ultrasound. As shown in Table 1, Doppler ultrasound results, in general, in higher values of I_SpTa. Ziskin and Petitti suggest that the existing data on exposure of the fetus in utero are inadequate to conclude that diagnostic ultrasound is safe at all combinations of dose and period of exposure for both imaging and Doppler devices.

Another point addressed by these researchers is the importance of statistical considerations, including sample size and statistical level of significance. Because a more thorough treatment of statistics is beyond the scope of this chapter, it can be simply stated that the larger the sample, the higher the statistical level of significance that can be achieved. The usefulness of small samples is extremely limited; studies that use small samples usually have inconclusive results.

In summary, the human studies that have been performed do not preclude the possibility that adverse effects may be found under certain conditions. The limited data available indicate that no relation has been found between prenatal exposure to ultrasound and subsequent postnatal changes in children, but statistical considerations show that minor chemical and behavioral changes, long-term delayed effects, and certain genetic effects could easily escape detection.² There is still a need for a well-designed, randomized clinical study addressing the risk for the fetus exposed in utero.

In general, the literature describing clinically relevant exposure conditions is rather limited, and few results, if any (even of experiments in vivo), can be immediately applied or extrapolated to discussions of clinical safety. The reason for this is the large number of variables that must be considered, which makes bioeffects experiments difficult to design and perform free from artifacts. Also, the number of subjects exposed to the ultrasound field is often limited, so the data obtained cannot be considered statistically significant.^2,3 It is worth reiterating that lung hemorrhage was produced in the lung of a macaque monkey whose chest was exposed to the maximum output level produced by a commercially available diagnostic scanner.²⁹ The mechanism of injury was determined to be a nonthermal one; the tissue damage appeared to be caused by gas volumes existing in the lung tissue. Although these findings were not confirmed by an independent laboratory, they indicate that caution should be used in diagnostic examinations related to echocardiographic and esophageal applications.

Results of experiments performed at exposure levels and durations higher than those used in diagnostic examinations are difficult to extrapolate to human examination conditions. In addition, reproducibility of the results presents a further limitation: often the bioeffects observed cannot be confirmed by an independent laboratory. It is conceivable that more uniform requirements regarding the determination of acoustic output parameters would facilitate comparison of the experiments between different laboratories.

The current evidence on ultrasonically induced bioeffects in the laboratory setting (with the possible exception of the results published in the article by Tarrantal and Canfield²⁹ and those pointed out in the article by Barnett and colleagues⁵) is not immediately applicable to the clinical situation. However, it is important to keep in mind that the uncertainties experienced in determining the intensity levels and the associated exposure conditions do not permit a categorical statement to be made regarding the unconditional safety of diagnostic ultrasound. It is also important to reiterate that the available data from both empirical and epidemiologic studies indicate that there is no verified evidence of adverse effects in patients caused by exposure to diagnostic levels of ultrasound (see Appendix).

Although these findings are consistent with almost three decades of clinical experience, it is also important to realize that the acoustic exposure levels in the available data may not be representative of the full range of current fetal exposure (see Table 1, Table 2 and Table 3). As already indicated, the acoustic outputs of diagnostic instruments have been increasing,^17,39 and recent laboratory studies indicate that tissue damage can occur at the exposure levels produced by commercially available equipment.⁵

Acoustic output measurements indicate that the peak rarefactional pressure amplitudes of some Doppler systems can exceed 4 MPa. Although such pressure amplitudes appear to be sufficient to cause adverse effects,²⁹ so far no evidence has been presented indicating any pulmonary extravasation after ultrasound exposure. However, these data indicate that appropriate caution should be exerted during neonatal examination, because even small amounts of extravasation can be of concern. In practice, this would require operators to follow the ALARA principle and to use the minimum transmitting acoustic power necessary to obtain adequate diagnostic data. The continuously updated display of the TI and MI should be of significant assistance here. As already mentioned, these indices provide information on the likelihood of an adverse biologic effect occurring from the ultrasound examination that is currently performed in clinical practice.⁷ The TI index provides real-time information indicating the worst-case temperature rise at the actual operating conditions of the imaging equipment. The MI index indicates the potential for cavitation phenomena to occur. If the predefined set value is exceeded, indicating the potential for harm, the clinician will be able to make an informed decision regarding the benefit/risk ratio of the given ultrasound examination. The decision may be influenced by factors that are not covered in the indices. These factors include consideration of the imaging site perfusion, patient obesity (which may severely restrict penetration depth), and a possible reduction in the exposure time by minimizing the duration of examination. A continuously updated on-screen display of the MI and TI indices is incorporated in recent designs of diagnostic ultrasound imaging equipment. It is appropriate to note that an output display is not required if the transducer and the system are not capable of exceeding an MI or TI of 1. However, if the transducer and system are capable of exceeding an MI or TI of 1, then the system must display values as low as 0.4 to assist the operator to implement the ALARA principle (see Appendix).⁷ It should be noted that the MI, which is defined as a derated (0.3 dB/cm/MHz) peak rarefactional pressure in MPa (ρ_r.3) divided by the square root of the center frequency in MHz, is not a perfect indicator. Although it simplifies the description of thresholds for bioeffects in tissues containing stabilized gas bodies, it may underestimate conditions in situ. Another limitation of the MI is that it describes conditions only at the focus. This may not be the primary point of interest, for instance in cardiological examinations. In this case, the most common way for the lung to be exposed during a diagnostic procedure is where the transducer is applied directly to the chest of the patient. Here, the focal region of the transducer is not within the lung tissue. An in-depth discussion of which index is most appropriate for a given examination, as well as a careful discussion of the limitations involved in implementing the ALARA principle with the use of these indices, is given in the article titled Medical Ultrasound Safety (also see Appendix).⁷

Overall, the clinical data are reassuring in that no established adverse effects on human patients exposed to diagnostic ultrasound examinations have been reported. However, the deficiencies of the data available and the tendency to increase the acoustic output power indicate the need for carefully planned experiments to provide safety information relevant to medical practice. Knowledge of the relevant ultrasound field parameters, such as the maximum peak pressure (with regard to both space and time), working or center frequency, pulse waveform, beam profile, and pulse repetition frequency, is essential for proper comparison of the experimental results. This knowledge, along with the actual exposure time, should be included in papers reporting on the biologic effects of ultrasound.

Analysis of the acoustic output data given in the previous sections indicates that the diagnostic procedure that introduces the greatest concern for thermal bioeffects is the use of PW Doppler in a fetal examination. Similarly, cavitation or a gas body - related mechanism is associated with B-scan imaging of the developing fetus.

This chapter concludes with a brief review of official AIUM statements (see Appendix). These statements were prepared by the AIUM Bioeffects Committee, whose expertise in the field is widely recognized in the ultrasound community throughout the world. The statements summarize the current knowledge on the physical mechanisms of interaction between ultrasound and biologic tissue and are based on both empirical and clinical data. The empirical data were scrutinized to detect possible dose - response relations regardless of the underlying mechanisms.

The data in the literature allow a fairly comprehensive statement on “Non-Human In Vivo Biologic Effects,” which covers both thermal and nonthermal mechanisms and provides guidelines to estimate potentially hazardous pressure amplitudes or intensity levels and exposure times.

In conclusion, diagnostic ultrasound has an excellent safety record. The clinical data are reassuring in that there is no report of damage to human patients from diagnostic ultrasound. However, it must be emphasized that neither theoretic calculations nor experimental results can yield unambiguous and definite evidence that fully guarantees the safety of ultrasound diagnostics. Because diagnostic ultrasound is an extremely powerful tool in the hands of experienced physicians and sonographers, the final decision regarding the risks and benefits can be made only by the individual responsible for applying the ultrasound to the patient.

Official Statement

Approved

March 1993

October 1982

CLINICAL SAFETY

Diagnostic ultrasound has been in use since the late 1950s. Given its known benefits and recognized efficacy for medical diagnosis, including use during human pregnancy, the American Institute of Ultrasound in Medicine herein addresses the clinical safety of such use:

No confirmed biological effects on patients or instrument operators caused by exposure at intensities typical of present diagnostic ultrasound instruments have ever been reported. Although the possibility exists that such biological effects may be identified in the future, current data indicate that the benefits to patients of the prudent use of diagnostic ultrasound outweigh the risks, if any, that may be present.

Official Statement

Approved

October 1992

August 1976

MAMMALIAN IN VIVO ULTRASONIC BIOLOGICAL EFFECTS

Information from experiments utilizing laboratory mammals has contributed significantly to our understanding of ultrasonically induced biological effects and the mechanisms that are most likely responsible. The following statement summarizes observations relative to specific ultrasound parameters and indices. The history and rationale for this statement are provided in Bioeffects and Safety of Diagnostic Ultrasound (AIUM, 1993).

In the low megahertz frequency range there have been no independently confirmed adverse biological effects in mammalian tissues exposed in vivo under experimental ultrasound conditions, as follows.

1. When a thermal mechanism is involved, these conditions are unfocused-beam intensities* below 100 mW/cm², focused-beam† intensities below 1 W/cm², or thermal index values less than 2. Furthermore, such effects have not been reported for higher values of thermal index when it is less than
   
   where t is exposure time ranging from 1 to 250 minutes, including off-time for pulsed exposure.
   
2. When a nonthermal mechanism is involved,# in tissues that contain well-defined gas bodies, these conditions are in situ peak rarefactional pressures below approximately 0.3 MPa or mechanical index values less than approximately 0.3. Furthermore, for other tissues no such effects have been reported.
   

Official Statement

Approved

March 1993

October 1987

CONCLUSIONS REGARDING GAS BODIES

1. The temporal peak outputs of some currently available diagnostic ultrasound devices can exceed the threshold for cavitation in vitro and can generate levels that produce extravasation of blood cells in the lungs of laboratory animals.
   
2. A Mechanical Index (MI)* has been formulated to assist users in evaluating the likelihood of cavitation-related adverse biological effects for diagnostically relevant exposures. The MI is a better indicator than derated spatial peak, pulse average intensity (I_SppA.3) or derated peak rarefactional pressure (ρ_r.3) for known adverse nonthermal biological effects of ultrasound.
   
3. Thresholds for adverse nonthermal effects depend upon tissue characteristics and ultrasound parameters such as pressure amplitude, pulse duration and frequency. Thus far, biologically significant, adverse, nonthermal effects have only been identified with certainty for diagnostically relevant exposures in tissues that have well-defined populations of stabilized gas bodies. For extravasation of blood cells in postnatal mouse lung, the threshold values of MI increase with decreasing pulse duration in the 1–100 μs range, increase with decreasing exposure time and are weakly dependent upon pulse repetition frequency. The threshold value of MI for extravasation of blood cells in mouse lung is approximately 0.3. The implications of these observations for human exposure are yet to be determined.
   
4. No extravasation of blood cells was found in mouse kidneys exposed to peak pressures in situ corresponding to an MI of 4. Furthermore, for diagnostically relevant exposures, no independently confirmed, biologically significant adverse nonthermal effects have been reported in mammalian tissues that do not contain well-defined gas bodies.
   

Official Statement

Approved

March 1995

CONCLUSIONS REGARDING EPIDEMIOLOGY

Based on the epidemiologic evidence to date and on current knowledge of interactive mechanisms, there is insufficient justification to warrant a conclusion that there is a causal relationship between diagnostic ultrasound and adverse effects.

Official Statement

Approved

March 1993,

October 1987

CONCLUSIONS REGARDING HEAT

1. Excessive temperature increase can result in toxic effects in mammalian systems. The biological effects observed depend on many factors, such as the exposure duration, the type of tissue exposed, its cellular proliferation rate, and its potential for regeneration. Age and stage of development are important factors when considering fetal and neonatal safety. Temperature increases of several degrees Celsius above the normal core range can occur naturally; there have been no significant biological effects observed resulting from such temperature increases except when they were sustained for extended time periods.
   1. For exposure durations up to 50 hours, there have been no significant biological effects observed due to temperature increases less than or equal to 2°C above normal.
      
   2. For temperature increases greater than 2°C above normal, there have been no significant biological effects observed due to temperature increases less than or equal to
      
      where t is the exposure duration ranging from 1 to 250 minutes. For example, for temperature increases of 4°C and 6°C, the corresponding limits for the exposure duration t are 16 min and 1 min, respectively.
      
   3. In general, adult tissues are more tolerant of temperature increases than fetal and neonatal tissues. Therefore, higher temperatures and/or longer exposure durations would be required for thermal damage.
      
   
   
2. The temperature increase during exposure of tissues to diagnostic ultrasound fields is dependent upon (a) output characteristics of the acoustic source such as frequency, source dimensions, scan rate, power, pulse repetition frequency, pulse duration, transducer self heating, exposure time and wave shape and (b) tissue properties such as attenuation, absorption, speed of sound, acoustic impedance, perfusion, thermal conductivity, thermal diffusivity, anatomical structure and nonlinearity parameter.
   
3. For similar exposure conditions, the expected temperature increase in bone is significantly greater than in soft tissues. For this reason, conditions where an acoustic beam impinges on ossifying fetal bone deserve special attention due to its close proximity to other developing tissues.
   
4. Calculations of the maximum temperature increase resulting from ultrasound exposure in vivo should not be assumed to be exact because of the uncertainties and approximations associated with the thermal, acoustic and structural characteristics of the tissues involved. However, experimental evidence shows that calculations are capable of predicting measured values within a factor of two. Thus, it appears reasonable to use calculations to obtain safety guidelines for clinical exposures where temperature measurements are not feasible. To provide a display of real-time estimates of tissue temperature increases as part of a diagnostic system, simplifying approximations are used to yield values called Thermal Indices.* Under most clinically relevant conditions, the soft-tissue thermal index, TIS, and the bone thermal index, TIB, either overestimate or closely approximate the best available estimate of the maximum temperature increase (ΔT_max). For example, if TIS = 2, then ΔT_max 2°C.
   
5. The current FDA regulatory limit for I_SPTA.3 is 720 mW/cm². For this, and lesser intensities, the best available estimate of the maximum temperature increase in the conceptus can exceed 2°C.
   
6. The soft-tissue thermal index, TIS, and the bone thermal index, TIB, are useful for estimating the temperature increase in vivo. For this purpose, these thermal indices are superior to any single ultrasonic field quantity such as the derated spatial-peak, temporal-average intensity, I_SPTA.3. That is, TIS and TIB track changes in the maximum temperature increases, ΔT_max, thus allowing for implementation of the ALARA principle, whereas I_SPTA.3 does not. For example,
   1. At a constant value of I_SPTA.3, TIS increases with increasing frequency and with increasing source diameter.
      
   2. At a constant value of I_SPTA.3, TIB increases with increasing focal beam diameter.
      
   
   

(Reprinted with permission of AIUM, 14750 Sweitzer Lane, Suite 100, Laurel, MD 20707–5906)

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